Functionally Distinct Transmission of Human Immunodeficiency Virus Type 1 Mediated by Immature and Mature Dendritic Cells

Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
Journal of Virology (Impact Factor: 4.44). 10/2007; 81(17):8933-43. DOI: 10.1128/JVI.00878-07
Source: PubMed


Dendritic cells (DCs) potently stimulate the transmission of human immunodeficiency virus type 1 (HIV-1) to CD4(+) T cells. Immature DCs (iDCs) located in submucosal tissues can capture HIV-1 and migrate to lymphoid tissues, where they become mature DCs (mDCs) for effective antigen presentation. DC maturation promotes HIV-1 transmission; however, the underlying mechanisms remain unclear. Here we have compared monocyte-derived iDCs and mDCs for their efficiencies and mechanisms of HIV-1 transmission. We have found that mDCs significantly facilitate HIV-1 endocytosis and efficiently concentrate HIV-1 at virological synapses, which contributes to mDC-enhanced viral transmission, at least in part. mDCs were more efficient than iDCs in transferring HIV-1 to various types of target cells independently of C-type lectins, which partially accounted for iDC-mediated HIV-1 transmission. Efficient HIV-1 trans-infection mediated by iDCs and mDCs required contact between DCs and target cells. Moreover, rapid HIV-1 degradation occurred in both iDCs and mDCs, which correlated with the lack of HIV-1 retention-mediated long-term viral transmission. Our results provide new insights into the mechanisms underlying DC-mediated HIV-1 transmission, suggesting that HIV-1 exploits mDCs to facilitate its dissemination within lymphoid tissues.

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    • "Previous studies indicate that AA metabolites affect monocytes in HIV positive drug users [33] and HIV-1 envelop protein gp120 induced viral replication subsequently affect the immune function in human DCs [40]. In the present study, IDC in cocaine using HIV infected subjects showed an increased level of AA metabolites COX-2, TBXA2 R and 5-LOX gene expression and protein modification with significant increase of PGE2 levels compared to normal subjects. "
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    ABSTRACT: Arachidonic acid (AA) is known to be increased in HIV infected patients and illicit drug users are linked with severity of viral replication, disease progression, and impaired immune functions. Studies have shown that cocaine accelerates HIV infection and disease progression mediated by immune cells. Dendritic cells (DC) are the first line of antigen presentation and defense against immune dysfunction. However, the role of cocaine use in HIV associated acceleration of AA secretion and its metabolites on immature dendritic cells (IDC) has not been elucidated yet. The aim of this study is to elucidate the mechanism of AA metabolites cyclooxygenase-2 (COX-2), prostaglandin E2 synthetase (PGE2), thromboxane A2 receptor (TBXA2R), cyclopentenone prostaglandins (CyPG), such as 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2), 14-3-3 ζ/δ and 5-lipoxygenase (5-LOX) mediated induction of IDC immune dysfunctions in cocaine using HIV positive patients. The plasma levels of AA, PGE2, 15d-PGJ2, 14-3-3 ζ/δ and IDC intracellular COX-2 and 5-LOX expression were assessed in cocaine users, HIV positive patients, HIV positive cocaine users and normal subjects. Results showed that plasma concentration levels of AA, PGE2 and COX-2, TBXA2R and 5-LOX in IDCs of HIV positive cocaine users were significantly higher whereas 15d-PGJ2 and 14-3-3 ζ/δ were significantly reduced compared to either HIV positive subjects or cocaine users alone. This report demonstrates that AA metabolites are capable of mediating the accelerative effects of cocaine on HIV infection and disease progression.
    PLoS ONE 08/2014; 9(8):e106348. DOI:10.1371/journal.pone.0106348 · 3.23 Impact Factor
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    • "However, DC-SIGN expression is reduced upon DC maturation [25], [49], [50], while HIV-1 capture and trans-infection are potently enhanced [23], [24], [29], [30]. DC-SIGN blocking agents such as mannan or anti-DC-SIGN antibodies have minimal effects on capture and transfer of HIV-1 by mDCs, while they completely abrogate viral capture and transfer in DC-SIGN-transfected cell lines [29], [30]. Furthermore, DC-SIGN is not expressed on the surface of blood myeloid DCs and Langerhans cells [5], [51], while these cells efficiently capture and trans-infect HIV-1, especially after maturation [29], [52]. "
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    ABSTRACT: Dendritic cells (DCs) are essential in order to combat invading viruses and trigger antiviral responses. Paradoxically, in the case of HIV-1, DCs might contribute to viral pathogenesis through trans-infection, a mechanism that promotes viral capture and transmission to target cells, especially after DC maturation. In this review, we highlight recent evidence identifying sialyllactose-containing gangliosides in the viral membrane and the cellular lectin Siglec-1 as critical determinants for HIV-1 capture and storage by mature DCs and for DC-mediated trans-infection of T cells. In contrast, DC-SIGN, long considered to be the main receptor for DC capture of HIV-1, plays a minor role in mature DC-mediated HIV-1 capture and trans-infection.
    PLoS Pathogens 07/2014; 10(7):e1004146. DOI:10.1371/journal.ppat.1004146 · 7.56 Impact Factor
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    • "On the other hand, HIV-1 replication in DCs, but not DC-SIGN, is required for long-term transfer of HIV from DCs to CD4+ T cells (Lore et al., 2005; Nobile et al., 2005; Burleigh et al., 2006; Wang et al., 2007). Although DCs can support only minimal replication of HIV-1 (DC restriction, see Restrictions in DCs), it is considered that the antigen-dependent close DC–T cell contact, forming IS, would support the efficient virus transmission followed by massive virus replication in CD4+ T cells (Tsunetsugu-Yokota et al., 1995; Lore et al., 2005). "
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    ABSTRACT: Although dendritic cells (DCs) represent a small cell population in the body, they have been recognized as professional antigen presenting cells and key players of both innate and acquired immunity. The recent expansion of basic knowledge concerning differentiation and function of various DC subsets will greatly help to understand the nature of protective immunity required in designing acquired immunodeficiency syndrome (AIDS) vaccines. However, human immunodeficiency virus (HIV) not only targets CD4(+) T cells but also myeloid cells, including macrophages and DC. When HIV infects DC, its replication is highly restricted in DC. Nevertheless, even a low level of HIV production is sufficient to enhance HIV replication in activated CD4(+) T cells, through antigen presentation activity by HIV-infected DC. Considering how antiviral immunity is initiated and memory response is maintained, such efficient DC-T cell transmission of HIV should play an important role in the disturbed immune responses associated with HIV infection. Recently, accessory proteins encoded by HIV have been shown to interact with various proteins in DC, and thereby affect DC-T cell transmission. In this review, we summarize the current understanding about DC biology, antiviral immune responses and DC restriction factors, all of which will be important issues for the development of an effective AIDS vaccine in the future.
    Frontiers in Microbiology 07/2013; 4:178. DOI:10.3389/fmicb.2013.00178 · 3.99 Impact Factor
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